A. Background Regarding to Nanoparticle Formation/Production
Nowadays, the active ingredient developers run out of new chemical entities with high solubility; most compounds that are approved or enter development processes are poorly soluble and/or have low permeability. The traditional approaches to increase the solubility and dissolution rate of these compounds are very limited. Chemical modification, like salt- or prodrug formation and inclusion of ionizable groups could result in higher performance of the active compounds. However, these structural modifications can lead to inactivity or instability of the active compounds in many cases. Conventional solid or liquid formulations (e.g.; micronization, milling, solid dispersion, liposomes) could also be useful tools for the researchers to increase the solubility of the compounds, but the efficiency of the formulation is far behind the chemical modification. Nevertheless, these conservative approaches are very time- and cost-consuming procedures with high failure rates.
Nanoformulation is currently one of the most progressive fields of the pharmaceutical industry to increase solubility, bioavailability as well as reduce food and side effects of such active ingredients.
Nanoformulation is the reduction of particles size down to below 200 nm. The reduction of particle size leads to significantly increased dissolution rate of the active ingredients, which in turn can lead to increases in bioavailability.
There are two main approaches to making nanoparticles: “top-down” and “bottom-up” technologies. The conventional top-down approach basically relies on mechanical attrition to render large crystalline particles into nanoparticles. The bottom-up approach relies on controlled precipitation. The process involves dissolving the drugs in a solvent and precipitation in a controlled manner to nanoparticles through addition of an antisolvent.
Technologies relying on milling (top-down) or high-pressure homogenization (mixture of uncontrolled-bottom-up and top-down) are cost and time consuming methods. Both processes require high energy. This means that a large number of active compounds cannot be nanoformulated with these approaches due to heat induced active form conversion. For example, salt or active compounds with low melting point cannot be milled or high-pressure homogenized. The scale-up (industrial applicability) of the high energy processes are difficult and limited in many cases. These technologies target only late stage formulation or reformulation of poorly soluble active compounds to improve their efficiency.
Nanoparticle compositions are described, for example, in US 20080214535, WO 2007147160, WO 2008044102, U.S. Pat. Nos. 5,145,684; 5,719,147; 6,048,859; 6,096,742 and 6,235,735 patents.
Process for the preparation of Aprepitant is described, for example, in WO/2008/104512, WO/2007/088483, WO/2007/147160, WO/2007/016582, WO/2007/112457, WO/2009/001203 and WO/2009/108828 patents.
The nanoparticles of active pharmaceutical compounds can be made using, for example, milling, homogenization, precipitation techniques, or supercritical fluid techniques, as is known in the art. Methods of making nanoparticulate compositions are also described in U.S. Pat. No. 5,718,388, U.S. Pat. No. 5,862,999, U.S. Pat. No. 5,665,331, U.S. Pat. No. 5,543,133, U.S. Pat. No. 5,534,270.
B. Background Regarding Aprepitant
Aprepitant is a substance P/neurokinin 1 (NK1) receptor antagonist, chemically described as 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one.
Its empirical formula is C23H21F7N4O3, and its structural formula is:

Aprepitant is a white to off-white crystalline solid, with a molecular weight of 534.43. It is practically insoluble in water. Aprepitant is sparingly soluble in ethanol and isopropyl acetate and slightly soluble in acetonitrile.
Each capsule of EMEND for oral administration contains either 40 mg, 80 mg, or 125 mg of Aprepitant and the following inactive ingredients: sucrose, microcrystalline cellulose, hydroxypropyl cellulose and sodium lauryl sulfate. The capsule shell excipients are gelatin, titanium dioxide, and may contain sodium lauryl sulfate and silicon dioxide. The 40-mg capsule shell also contains yellow ferric oxide, and the 125-mg capsule also contains red ferric oxide and yellow ferric oxide.
Pharmacokinetics
Absorption
Following oral administration of a single 40 mg dose of EMEND in the fasted state, mean area under the plasma concentration-time curve (AUC0-∞) was 7.8 mcg•hr/mL and mean peak plasma concentration (Cmax) was 0.7 mcg/mL, occurring at approximately 3 hours postdose (tmax). The absolute bioavailability at the 40-mg dose has not been determined.
Following oral administration of a single 125-mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24h was approximately 19.6 mcg•hr/mL and 21.2 mcg•hr/mL on Day 1 and Day 3, respectively. The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively. At the dose range of 80-125 mg, the mean absolute oral bioavailability of Aprepitant is approximately 60 to 65%. Oral administration of the capsule with a standard high-fat breakfast had no clinically meaningful effect on the bioavailability of Aprepitant.
Metabolism
Aprepitant undergoes extensive metabolism. In vitro studies using human liver microsomes indicate that Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Metabolism is largely via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6, CYP2C9, or CYP2E1 was detected. In healthy young adults, Aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300 mg dose of [14C]-Aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of Aprepitant, which are only weakly active, have been identified in human plasma.
Side Effects
The following side effects have been reported in general use with Aprepitant: allergic reactions, which may be serious, and may include hives, rash and itching and cause difficulty in breathing or swallowing.
Because of the insolubility of Aprepitant in biological relevant media and significant fed/fasted effect, there is a need in the art to enhance bioavailability in the fasted condition/increase the absorption in fasted condition/faster onset of action and reduce the dosage in order to overcome the problems associated with prior conventional Aprepitant formulations. These problems can be solved by novel nanostructured particle formation of Aprepitant characterized by increased solubility/dissolution rate, decreased fed/fasted effect, bioequivalence or higher Cmax and faster onset of action compared to reference active compound and/or to the marketed drug described in the present invention. The present invention satisfies this need.